Ronald F. Wolf

Growth hormone and insulin reverse net whole body and skeletal muscle protein catabolism in cancer patients.

The authors examined the effect of recombinant-human growth hormone (r-hGH) and insulin (INS) administration on protein kinetics in cancer patients. Twenty-eight cancer patients either received r-hGH for 3 days (GH group, n = 12, weight loss = 6 +/- 2%) or were not treated (control [CTL] group, n = 16, weight loss = 11 +/- 2%) before metabolic study. Recombinant-human growth hormone dose was 0.1 mg/kg/day (n = 6) or 0.2 mg/kg/day (n = 6). Patients then underwent measurement of baseline protein kinetics (GH/B, CTL/B) followed by a 2-hour euglycemic insulin infusion (1 mU/kg/minute) and repeat kinetic measurements (GH/INS,CTL/INS). Whole-body protein net balance (mumol leucine/kg/minute) was higher (p less than 0.05) in GH/INS (0.20 +/- 0.06) than in CTL/INS (0.06 +/- 0.03) or GH/B (-0.19 +/- 0.03). Skeletal muscle protein net balance (nmol phenylalanine/100 g/minute) in GH/INS (25 +/- 6) and CTL/INS (19 +/- 5) was higher than CTL/B (-18 +/- 3). Recombinant-human growth hormone and insulin reduce whole-body and skeletal muscle protein loss in cancer patients. Simultaneous use of these agents during nutritional therapy may benefit the cancer patient.

The effect of systemic hyperinsulinemia with concomitant amino acid infusion on skeletal muscle protein turnover in the human forearm

In vitro, insulin has been shown to increase skeletal muscle (SM) protein synthesis and decrease SM protein breakdown. Whether these same effects are found in vivo in man is less clear. The study of the effect of hyperinsulinemia (INS) on SM protein turnover (SMPT) is complicated by hypoaminoacidemia, which can obviate the true effect of insulin on SMPT. To prevent this, we studied the effect of INS on SMPT in the human forearm with amino acid (AA) infusion to ensure adequate substrate for full evaluation of insulins effect. Twelve healthy volunteers (aged 53 +/- 3 years) were studied. Steady-state AA kinetics were measured across the forearm after a systemic 2-hour primed continuous infusion of 3H-phenylalanine (3H-Phe) and 14C-leucine (14C-Leu) in the postabsorptive (PA) state and in response to systemic INS (71 +/- 5 microU/mL). AAs were infused during INS as 10% Travasol (Travenol Laboratories, Deerfield, IL) at .011 mL/kg/min to maintain PA branched-chain AA (BCAA) levels, known regulators of SMPT, and to mildly elevate total AA levels. The negative PA net balance of both Phe and total Leu carbons (LeuC) became positive with INS + AA infusion (Phe from -16 +/- 2 to 12 +/- 3 nmol/min/100 g [P < .01]; LeuC from -26 +/- 6 to 24 +/- 7 nmol/min/100 g [P < .01]).(ABSTRACT TRUNCATED AT 250 WORDS)

Impact of Clinicopathologic Parameters on Patient Survival in Carcinoma of the Cervical Esophagus

BACKGROUND The survival of patients with carcinoma of the cervical esophagus remains poor in spite of multimodality treatment and technical improvements in surgical resection and reconstruction. This study was undertaken to update our experience with cervical esophageal carcinoma and to identify factors that had an impact on patient survival and quality of life. PATIENTS AND METHODS Clinical data encompassing 132 variables were collected on 67 patients with cervical esophageal carcinoma from 1980 to 1993. Statistical analysis was performed: independent Students t-tests, Cox regression, Kaplan-Meier curves, and log rank analyses were used in the statistical evaluation. The mean age of the patients was 63 years (range 31 to 88). Dysphagia was the primary symptom in 86% of patients; 80% had received no prior treatment. The most common abnormal finding (21%) on physical examination was a neck mass. RESULTS Curative resection was performed in 22 patients, 7 had palliative procedures, and 7 were found to be inoperable at exploration and received palliative treatment. Radiation with or without chemotherapy was definitive treatment for 10 patients, whereas 4 patients were treated with chemotherapy alone for cure, and 17 patients received palliative treatment. The mean survival following diagnosis was 17 months (range 1 to 96). Cumulative 5-year survival was 12%. CONCLUSIONS Persistent disease, chemotherapy prior to presentation, and chemotherapy for cure remained as statistically significant parameters associated with decreased survival by multivariate analysis. There was a trend toward improved survival in patients treated with surgical resection.

The effect of insulin on glucose and protein metabolism in the forearm of cancer patients

This study was designed to study the effect of systemic hyperinsulinaemia (INS) on glucose and protein metabolism in cancer patients. Sixteen cancer patients (8 > 10% weight loss (WL); 8 < 10% weight loss (NWL)) were compared with 12 healthy controls. Glucose uptake (GU) and phenylalanine (PHE) exchange kinetics were measured across the forearm in the postabsorptive state (PA) and in response to INS (71 +/- 5 microU ml-1). At steady state in response to INS, the negative PA PHE net balance became significantly positive, and GU significantly increased, for cancer and control groups, with no significant differences between the two groups. Subset analysis of NWL cancer vs. WL cancer found no difference between WL and NWL for the change in PHE balance from PA and INS, however GU increased significantly only for the NWL group between PA and INS. These data indicate that cancer patients are not resistant to the anabolic effect of INS on protein metabolism, regardless of weight loss, but are resistant to the effect of INS on glucose metabolism when further along in the disease process as evident by more significant weight loss. This differential response to the effect of INS can be exploited in an attempt to promote protein accrual in weight-losing cancer patients.

Effect of growth hormone on tumor and host in an animal model

Background: The relative effects of growth hormone on tumor versus host growth and protein metabolism are not known. This study examines the influence of recombinant rat growth hormone (r-rGH) on host and tumor growth, host body composition, and protein synthesis of tumor and host in tumor-bearing rats.Methods: After left flank implantation of methylcholanthrene-induced sarcoma, 28 Fischer rats with palpable tumor were treated with s.c. saline or 1 mg/kg/day r-rGH for 11 days. At death, fractional protein synthetic rates (FSRs) of tumor, liver, and gastrocnemius muscle were determined. In a separate experiment, 27 tumor-bearing rats received saline or 1 mg/kg/day r-rGH for 2 weeks. Tumor and host growth and host body composition were analyzed.Results: Animals treated with r-rGH had significantly higher liver FSR than did controls (233 ± 27%/day vs. 110 ± 4%/day, respectively). No significant differences were associated with growth hormone administration with respect to tumor growth, host composition, or FSR of tumor or muscle.Conclusions: Growth hormone stimulates liver protein synthesis, without changing tumor growth, protein synthesis, or host composition in this rat sarcoma model. Further investigation of growth hormone as an anticachectic agent is warranted.

Effect of systemic insulin on protein kinetics in postoperative cancer patients.

Background: Cancer cachexia is a significant cause of postoperative morbidity and mortality in patients with tumors of the upper gastrointestinal tract. Standard parenteral nutrition (TPN) has failed to alter this. The anabolic effect of insulin has been well documented, and its positive effect on protein economy in cancer patients has been recently demonstrated. This study examines the effect of high-dose insulin and parenteral nutrition on protein kinetics in postoperative cancer patients.Methods: Eleven patients underwent surgery for pancreatic, esophageal, or gastric carcinoma. Postoperatively, patients received standard TPN for 4 days (1 g/kg/day amino acids, 1,000 kcal/day dextrose, 100 g/day lipid), and hyperinsulinemic parenteral nutrition for 4 days (same as standard TPN plus 1.44 U/kg/day regular human insulin) in a crossover design. All patients received both treatments, and the order of treatment was determined randomly. Euglycemia was maintained during insulin infusion via a variable 30% dextrose infusion. Patients underwent protein metabolic studies after each treatment period and rates of whole body and skeletal muscle protein synthesis, breakdown, and net balance were determined by radioisotopic tracer methods using14C-leucine and3H-phenylalanine.Results: Compared with standard TPN (STD), hyperinsulinemic TPN (INS) resulted in a significant increase in skeletal muscle protein synthesis (INS: 52.04±10.22 versus STD: 26.06±6.71 nmol phe/100 g/min, p<0.05) and net balance of protein (INS: 7.75±4.61 versus STD: −15.10±6.44 nmol phe/100 g/min, p<0.01), but no difference in skeletal muscle protein breakdown (INS: 44.29±11.54 versus STD: 41.17±5.89 nmol phe/100 g/min). Whole-body net balance of protein also significantly increased with insulin-based TPN, compared with standard TPN (INS: 0.04±0.05 versus STD: −0.08±0.07 µmol leu/kg/min, p<0.05), but no difference in whole-body protein synthesis (INS: 2.52±0.15 versus STD: 2.49±0.15 µmol leu/kg/min) or whole-body protein breakdown (INS: 2.48±0.16 versus STD: 2.58±0.19 µmol leu/kg/min) was observed. Patients received significantly more calories during the hyperinsulinemic TPN period than during the standard TPN period. There was no difference in total, essential, or branched-chain amino acids, and no difference in serum free fatty acids, triglycerides, or cholesterol was observed between the two treatment periods.Conclusion: High-dose insulin in conjunction with hypercaloric parenteral nutrition causes improved skeletal muscle protein synthesis, skeletal muscle protein net balance, and whole-body protein net balance compared with standard TPN in postoperative cancer patients.

The miniscule benefit of serial carcinoembryonic antigen monitoring after effective curative treatment for primary colorectal cancer.

BACKGROUND Serial carcinoembryonic antigen (CEA) levels have been recommended to detect asymptomatic recurrent colorectal cancer and to facilitate curative additional therapy. This study was designed to investigate the outcome of additional treatment for recurrent cancer in patients undergoing primary colorectal cancer treatment in a specialty center and subsequent relapsing with an elevation in serum CEA. STUDY DESIGN Patients treated for their primary cancers at our institution whose followup included CEA monitoring and whose cancers subsequently recurred, were analyzed from a prospective database of almost 1,900 patients. CEA levels of > or = 5 ng/mL were considered elevated for purposes of treatment results. One hundred sixty-three patients were suitable for analysis. Median followup before and after recurrence was 14 months and 16 months, respectively. RESULTS Fifty patients were able to undergo complete resection of their recurrence, and 26 of these patients are without evidence of recurrence at last followup. Two-thirds of recurrences were associated with an elevation of CEA; this elevation at recurrence was associated with decreased survival (p < 0.05, Kaplan Meier). Of the 109 patients with an elevation of CEA at recurrence, complete re-resection was accomplished in 26 patients. Of these, half remain cancer free. Of those with a normal CEA at recurrence, complete re-resection was feasible in 24 patients. CONCLUSIONS Only 17% of patients with recurrent colorectal cancer undergoing potentially curative reresection have an elevated CEA. If we use the denominator of our patient population using an estimated relapse rate of 25-50%, the overall likelihood of CEA-directed curative re-resection confirms early estimates of less than a 5% survival advantage.

Effect of perioperative blood transfusion on recurrence and survival in 232 primary high-grade extremity sarcoma patients

AbstractBackground: Allogeneic blood transfusion (BT) has been implicated as an unfavorable factor influencing cancer recurrence and overall survival. Methods: To investigate this, 232 consecutive localized, high-grade extremity soft tissue sarcoma (STS) patients admitted between January 1, 1983, and December 31, 1989, were analyzed from our prospective database by univariable and Cox multivariable statistical methods. Results: Twenty-eight patients developed a local recurrence (LR). Factors found significantly unfavorable for the rate of developing an LR by uni- and multivariable tests were age >60 years and positive microscopic margin. Eighty-nine patients developed a distant metastasis (DM) and 72 patients died of their tumor. Median follow-up of survivors was 48 months. Unfavorable factors for DM and tumor mortality (TM) by univariable analysis included large size, deep tumor (that involved or was below the superficial fascia), positive microscopic margin, invasion of a vital structure, operative blood loss, duration of operation, and perioperative BT (whole blood or packed cells -24 to +48 h of curative operation). Multivariable analysis found large size, deep tumor, and positive margin significant independent unfavorable factors for DM and TM. The effect of BT was not a significant independent prognosticator for LR, DM, or TM by multivariable analysis (p=0.26, 0.56, 0.08, respectively), The only factor that was found to be significant in a multivariable analysis of factors contributing to postmetastasis survival was time <6 months until metastasis (p=0.008). BT had no significant impact on postmetastasis survival (p=0.42). There was a significant association between BT and deep, large tumors. As the size of deep tumors increased from <5, ≥5<10, ≥10<15, or≥15 cm, the amount transfused was 15, 16, 49, and 68% (p<0.00001). Also, BT was significantly (p<0.005) associated with low hematocrit at initial diagnosis, blood loss during surgery, and the length of the surgical procedure. Conclusions: These data emphasize the importance of size, depth, and margin on distant recurrence and death for localized high-grade extremity STS. In the absence of a randomized trial, the impact of allogeneic blood transfusion would appear to be due to its strong association with large size and deep tumor invasion. This study also highlights the importance of a multivariable analysis and long-term follow-up to better define this controversial question.